Phosphorylation Increases Persistence Length and End-to-End Distance of a Segment of Tau Protein
Phosphorylation Increases Persistence Length and End-to-End Distance of a Segment of Tau Protein
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DOI：
10.1016/j.bpj.2015.12.013
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发表时间：
2016-01-19
影响因子：
3.4
通讯作者：
Hilser, Vincent J.
中科院分区：
文献类型：
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作者：
Chin, Alexander F.;Toptygin, Dmitri;Hilser, Vincent J.
蛋白质的内在无序区域在生理条件下缺乏独特的三级结构，富含磷酸化位点，并明显偏向于聚脯氨酸II构象。这种翻译后调控信号与非结构化区域内局部构象偏差的过度重合提出了一个问题：磷酸化是否可以操纵无序蛋白质的构象偏好？在这项研究中，我们使用时间分辨荧光共振能量转移和据我们所知的一种新颖的数据分析方法来直接测量源自人类微管相关蛋白tau的可磷酸化肽的端到端距离分布。我们的研究结果表明，苏氨酸或丝氨酸的磷酸化延长了端到端距离，并增加了测试模型肽的有效持续长度。出乎意料的是，延伸与盐浓度无关，暗示非静电起源。磷酸化延伸和硬化效应为在无序蛋白中发现的高度丰富的蛋白-蛋白相互作用的翻译后调控提供了肽级的物理解释，以及对tau蛋白微管结合活性的调控机制的潜在见解。
Intrinsically disordered regions of proteins, which lack unique tertiary structure under physiological conditions, are enriched in phosphorylation sites and in significant local bias toward the polyproline II conformation. The overrepresented coincidence of this posttranslational regulatory signal and local conformational bias within unstructured regions raises a question: can phosphorylation serve to manipulate the conformational preferences of a disordered protein? In this study, we use time-resolved fluorescence resonance energy transfer and a, to our knowledge, novel data analysis method to directly measure the end-to-end distance distribution of a phosphorylatable peptide derived from the human microtubule associated protein tau. Our results show that phosphorylation at threonine or serine extends the end-to-end distance and increases the effective persistence length of the tested model peptides. Unexpectedly, the extension is independent of salt concentration, suggestive of a nonelectrostatic origin. The phosphorylation extension and stiffening effect provides a peptide-scale physical interpretation for the posttranslational regulation of the highly abundant protein-protein interactions found in disordered proteins, as well as a potential insight into the regulatory mechanism of the tau protein's microtubule binding activity.